The long-term goal of this proposal is to elucidate the mechanism of action of decorin in controlling cell proliferation. The central hypothesis is that decorin is a natural antagonist of cancer growth, a working theory based on several key observations: [a] Decorin levels are suppressed in most transformed cells, but markedly increased in quiescent cells. [b] Animals harboring a targeted disruption of decorin and p53 genes die rapidly of thymic lymphomas, indicating that lack of decorin is permissive for tumorigenesis. [c] Ectopic expression of decorin induces profound cytostatic effects in a wide variety of transformed cells. [d] Decorin interacts with the epidermal growth factor receptor (EGFR) and causes a profound attenuation of its tyrosine kinase activity, thereby leading to growth inhibition. Over the next five years we plan to continue the studies on the biology of mammalian decorin and decode the molecular mechanisms through which decorin exerts its cytostatic functions. Specifically, we plan to: (1) Decipher the mechanism of action of decorin in suppressing EGFR activity. (2) Determine the precise structural requirements for decorin/EGFR interaction, and (3) Investigate the in vivo function of decorin as an anti-oncogenic factor. These concerted research lines should firmly establish the functional roles of decorin in tumorigenicity and shed light on its mechanism of action. The discovery that decorin is a novel biological ligand for the EGFR and that this interaction leads to an overt attenuation of the EGFR kinase and signaling provides the first demonstration of a secreted proteoglycan interacting with this important signal transducing pathway. The expected results could open novel perspectives for basic cancer research, and could lead to future approaches of cancer prevention and treatment directed at boosting the expression of this proteoglycan, thereby increasing a natural inhibitor of tumor cell growth.